Patent EA-002272-B1 (EA)
Title: Substituted indazole derivatives and theit use as inhibitors phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnp)
Inventor: MAFRAT ANTHONY
IPC: C07D/
Filed: 1997-04-01
Abstract: 1. A compound of the formula I   or a pharmaceutically acceptable salts thereof, wherein: R is hydrogen, -(CH2)n(C3-C7 cycloalkyl) wherein n is 0, or phenyl optionally substituted with 1-3 halo; R1 is C1-C7 alkyl; R2 is selected from the group consisting of    wherein the dashed line in formulas (la) and (Ib) represent a single bond; m is 0 to 4; R3 is cyano or CH2CN; R4 is H, CO2R14, C(Y)NR17R14, CN, CR9R10OR14; R5 is OH, R9, CH2OR9, CO2R9, C(O)NR9R10; or R4 or R5 are taken together with formation =O or =R8; R6 is C(O)OCH3; R7 is CR9R10OR14, CO2R14, C(Y)NR17R14, CN; R8 is 2-(1,3-dithian); each R9 and R10 is independently hydrogen or C1-C4 alkyl; each R14 is independently hydrogen or R15, each R15 is independently C1-C6 alkyl; each R17 is independently R10, R18 is H or C(O)OCH3; each Y is independently =O; 2. The compound of Claim 1 wherein R is cyclohexyl, cyclopentyl, or 4-fluoro-phenyl. 3. The compound of Claim 2 wherein R1 is C1-C2 alkyl. 4. The compound of Claim 3 wherein R1 is ethyl. 5. The compound of Claim 3 wherein R2 is a group of formula (la) wherein the dashed line represents a single bond. 6. The compound of Claim 5 wherein R3 is cyano. 7. The compound of Claim 6 wherein m is 0 and R5 is hydrogen. 8. The compound of Claim 6 wherein R4 is carboxy, or -CH2OH. 9. The compound of Claim 1 wherein R2 is a group of formula (la) wherein R3 and R5 are cis as follows:   10. The compound of Claim 1 wherein R2 is a group of formula (la) wherein the dashed line represents a single bond and R3 and R4 are cis. 11. The compound of Claim 1 selected from the group consisting of: 1-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanecarbonitrile; trans-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylic acid methyl ester; cis-4-cyano-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylic acid methyl ester; 1-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-4-oxo-cyclohexanacarbonitrile; cis-4-cyano-4-(l-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylic acid methyl ester; trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylic acid methyl ester; cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylic acid; trans-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)-cyclohexanecarboxylic acid; 1-(cyclohexyl-3-ethyl-1H-indazole-6-yl)-cis-4-hydroxylmethylcyclohexane carbonitrile; cis-4-cyano-4-(1-(cyclohexyl-3-ethyl)-1H-indazol-6-yl)-cyclohexanecarboxylic acid amide; and, trans-4-cyano-4-(1-(cyclohexyl-3-ethyl)-1H-indazol-6-yl)-cyclohexanecarboxylic acid amide. 12. A compound of the formula   wherein R is hydrogen, -(CH2)n(C3-C7cycloalkyl) wherein n is 0 or phenyl, optionally substituted with 1-3 halo; R1 is C1-C7 alkyl, X is bromo-, -C(O)O(C1-C6 alkyl), -CH2CN, carboxy, -CH2OH, or -C(O)H. with proviso that when X is bromo or carboxy or -C(O)O(C1-C6 alkyl), then R is not hydrogen, and R1 is not methyl. 13. The compound of Claim 12 wherein R is cyclohexyl, cyclopentyl, or 4-fluorophenyl and R1 is ethyl. 14. The compound of Claim 13 wherein X is bromo-. 15. A compound of the formula   wherein R is hydrogen, -(CH2)n(C3-C7cycloalkyl) wherein n is 0 or phenyl, optionally substituted with 1-3 halo; R1 is C1-C7 alkyl, 16. The compound of Claim 15 wherein R is cyclohexyl, cyclopentyl, or 4-fluoro-phenyl and R1 is ethyl. 17. A pharmaceutical composition for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in a mammal comprising a therapeutically-effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier. 18. A method for the inhibition of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in a mammal which comprises administering to said mammal a therapeutically-effective amount of the compound of Claim 1. 19. A pharmaceutical composition for the prevention or treatment of asthma, joint inflammation, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebal malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft versus host reaction, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, HIV, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, multiple sclerosis, type 1 diabetes mellitus, autoimmune diabetes, systemic lupus erythematosis, bronchitis, chronic obstructive airway disease, psoriasis, Bechet's disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease, leukemia, allergic rhinitis, or dermatitis, in a mammal, comprising a therapeutically-effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier. 20. A method for treating asthma, joint inflammation, rheumatoid arthritis, gouty arthritis, rheumatoid spondylitis, osteoarthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebal malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to inflection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to human acquired immune deficiency syndrome (AIDS), AIDS, HIV, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, multiple sclerosis, type 1 diabetes mellitus, autoimmune diabetes, systemic lupus erythematosis, bronchitis, chronic obstructive airway disease, psoriasis, Bechet's disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease, leukemia, allergic rhinitis, or dermatitis in a mammal which comprises administering to said mammal a therapeutically-effective amount of the compound of Claim 1.